US9056897B2 - Method for isolating a cyclohexapeptide - Google Patents

Method for isolating a cyclohexapeptide Download PDF

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US9056897B2
US9056897B2 US13/876,227 US201113876227A US9056897B2 US 9056897 B2 US9056897 B2 US 9056897B2 US 201113876227 A US201113876227 A US 201113876227A US 9056897 B2 US9056897 B2 US 9056897B2
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caspofungin
solution
resin
water
theta
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US20130184433A1 (en
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Robertus Mattheus De Pater
Dhiredj Chandre Jagesar
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Centrient Pharmaceuticals Netherlands BV
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DSM Sinochem Pharmaceuticals Netherlands BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links

Definitions

  • the present invention relates to a method for isolating a cyclohexapeptide and to a novel crystalline form of caspofungin diacetate thus obtained.
  • Cyclopeptides are polypeptides in which the terminal amine and carboxyl groups form an internal peptide bond.
  • Several cyclopeptides are known for their advantageous medicinal properties.
  • An excellent example of this is the class of echinocandins which are potent antifungals.
  • Cyclopeptides can be naturally occurring compounds but may also be obtained by total synthesis or by synthetic or genetic modification of naturally occurring or naturally produced precursors; the latter class is referred to as semi synthetic cyclopeptides.
  • Examples of medicinally useful echinocandins are the cyclohexapeptides anidulafungin, caspofungin, cilofungin and micafungin which are useful in treating fungal infections especially those caused by Aspergillus, Blastomyces, Candida, Coccidioides and Histoplasma .
  • R 1 —OH
  • R 2 —C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3
  • R 3 —H
  • R 4 —CH 2 C(O)NH 2
  • R 5 —H
  • Examples are compounds having an additional methyl function (such as pneumocandin A 0 , pneumocandin A 1 , pneumocandin A 2 , pneumocandin A 3 , pneumocandin A 4 , pneumocandin A 5 , pneumocandin A 6 ), compounds lacking one or two hydroxyl groups (such as pneumocandin B 1 , pneumocandin B 2 , pneumocandin B 5 , pneumocandin B 6 , pneumocandin E 0 ), compounds having a 4-hydroxy proline rather than a 3-hydroxy proline moiety (pneumocandin C 0 ), compounds having additional hydroxyl groups (such as pneumocandin D 0 , pneumocandin D 2 ) or the recently described impurity A (US 2009/0324635) wherein, in the caspofungin structure, one of the hydroxy-L-ornithine moieties is replaced by an L-serine moiety.
  • a method for isolating a cyclohexapeptide comprising the subsequent steps of:
  • the cyclohexapeptide obtained after step (f) may be dried in order to obtain a product with a reduced content of water.
  • the advantage of an additional drying procedure is that the resulting product is more easily handled, is less prone to the formation of unwanted impurities and is consequently of higher purity.
  • Said drying may be carried out by procedures known to the skilled person such as heating, applying reduced pressure, passing a stream of a gas over the isolated product or combinations thereof. Heating may be from temperatures ranging from 15° C. to 80° C. or from 20° C. to 60° C. or from 30° C. to 40° C.
  • Suitable gases are air or inert gasses such as nitrogen or noble gases such as argon, helium, neon or xenon.
  • R 1 may be —OR 6 or —NH(CH 2 ) 2 NHR 7 with R 6 is —H or an acyl, alkyl, aryl, thioalkyl or thioaryl group such as 4-methoxythiophenyl and thiophenyl and R 7 is —H or an acyl, alkyl or aryl group.
  • R 2 may be —H or C(O)R 8 with R 8 is —H or a group comprising from 10 to 25 carbon atoms such as -pC 6 H 4 -pC 6 H 4 -pC 6 H 4 —O(CH 2 ) 4 CH 3 , —(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 or -[4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl]-L-ornithine].
  • R 3 may be —OH or —H.
  • R 4 may be —CH 3 or —(CH 2 ) 2 NHR 7 or —CH 2 C(O)NHR 7 with R 7 as described above.
  • R 5 may be —CH 3 or —H.
  • cyclohexapeptides described above may be prepared following procedures known to the skilled person such as total chemical synthesis or semi-synthesis, i.e. fermentation followed by one or more chemical conversions.
  • One example may be the conversion of pneumocandin B 0 into caspofungin through phenylthio pneumocandin B 0 amine as described in U.S. Pat. No. 5,552,521 or U.S. Pat. No. 5,936,062.
  • the resin may be any chromatographic material such as hydrophobic interaction chromatography material, reversed phase chromatography material, ion-exchange chromatography material or a mixture of two or more of these materials.
  • resins suitable for the purpose of the present invention are Amberchrom XT 30, Amberchrom CG 300S, Amberchrom CG 300sd, Amberchrom CG 300XT, Amberchrom CG-71, Amberchrom CG-161, Toyopearl's Butyl-650, Ether-650, Hexyl-650, Phenyl-650 and the like.
  • the cyclohexapeptide may be contacted with the resin in various ways.
  • This may be achieved by combining a solution, such as an aqueous solution, of the cyclohexapeptide with the resin in a vessel.
  • the resulting mixture may be stirred to improve adsorption. Removal of resin and/or liquid in the subsequent may be performed by centrifugation, filtration or sedimentation or similar techniques.
  • the resin may be packed into a column and the solution of the cyclohexapeptide may be brought onto the column.
  • the resin may be washed after the solution of the cyclohexapeptide has been contacted with the resin in step (a). Such a washing step will remove impurities that do not adsorb to the resin.
  • the washing may be carried out with various solvents; for most cyclohexapeptides water or a mixture of water with a water-miscible solvent is preferred.
  • Water-miscible solvent in this respect refers to a solvent in which the solubility of water is at least 5% (w/w). Examples are alcohols, ketones, acetonitrile and the like. Specifically short-chain alcohols may be used, examples of which are ethanol, isopropanol, n-propanol and methanol.
  • the washing step should be performed before elution step (c) and may be performed before or after removal of the liquid in step (b).
  • the solution used in step (a) may also contain a water-miscible solvent.
  • the organic solvent used for elution in step (c) may be a water-miscible organic solvent.
  • the solvent may be mixed with water such as for example mixtures of ethanol/water wherein the amount of water is from 1-20% (w/w) or from 5-15% (w/w).
  • the solvents used in steps (a) and (c) may be the same but can also be different. The latter is a great advantage as it gives high flexibility when a switch from one solvent to the other is required.
  • a first solvent may be preferable for synthetic purposes whereas another, second, solvent may be preferable for crystallization purposes.
  • concentration of the cyclohexapeptide in solution before applying the method i.e. as in step (a)
  • concentration of said cyclohexapeptide in the solution of step (a) may be from 2 to 50 times lower than the concentration of said cyclohexapeptide in the solution retained after removal of said resin in step (d).
  • concentration of said cyclohexapeptide in the solution of step (a) may be from 2 to 50 times lower than the concentration of said cyclohexapeptide in the solution retained after removal of said resin in step (d).
  • an increase in concentration is advantageous for the subsequent crystallization and isolation steps (e) and (f) as loss of product in the mother liquor is reduced.
  • the concentration of said cyclohexapeptide in step (a) may be from 0.1 to 5 g ⁇ l ⁇ 1 where the concentration of said cyclohexapeptide in the solution retained after removal of the resin in step (d) may be from 5 to 40 g ⁇ l ⁇ 1 .
  • the latter concentration range still is relatively low as crystallization of cyclohexapeptides from solutions having concentrations ranging from 5 to 40 g ⁇ l ⁇ 1 has not been reported yet.
  • isolation such as crystallization
  • step (d) without intermediate concentration step, a methodology described in prior art documents.
  • the present approach avoids this additional process step which leads to a decrease in yield loss and lesser impurities.
  • the liquid wherein the cyclohexapeptide is dissolved may be replaced or partially replaced with another liquid during the method of the present invention.
  • This may be advantageous for controlling yield and purity of the final crystalline product.
  • the amount of water in the solution of step (a) may be from 75% to 95% whereas the amount of water in the solution retained after removal of the resin in step (d) may be less than 10%, for example 5% or even less than 0.5%. Consequently the present invention advantageously provides a method through which highly diluted cyclohexapeptides can be isolated in good to high yields.
  • the method is simple, does not require expensive and/or complex equipment and does not require energy-consuming evaporation techniques. In addition the conditions are mild thereby preventing unwanted degradation of the fragile cyclohexapeptides.
  • the final cyclohexapeptides may be in the form of pharmaceutically acceptable salts derived from acids such as acetic acid, arachidonic acid, citric acid, glutamic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, oxalic acid, palmitic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and trifluoroacetic acid or bases such as calcium hydroxide, potassium hydroxide and sodium hydroxide.
  • a salt which may be used for caspofungin (1b) is the diacetate
  • a salt that may be used for micafungin (1c) is the sodium salt.
  • the crystalline form of caspofungin diacetate of the present invention has a novel morphology resulting from the crystallization approach of the first aspect.
  • the present crystalline form of caspofungin diacetate does not reveal a distinct peak in the region 9.0 ⁇ 0.2 degrees 2-theta.
  • the ratio between the intensity of the most intense peak (at 2.92 ⁇ 0.2 degrees 2-theta) and the intensity of any peak in the region 9.0 ⁇ 0.2 degrees 2-theta is at least 10. In the sample depicted in FIG. 1 this is 18.
  • the water content of the crystalline caspofungin diacetate of the present invention may be from 0.1% to 10% (w/w).
  • Examples of ranges of water content in the cyclohexapeptides of the present invention are from 0.1% to 6% (w/w), from 1% to 8% (w/w), from 2 to 6% (w/w) or from 3.5% to 5.5% (w/w).
  • the crystalline caspofungin diacetate of the present invention has a purity of at least 99.0% as determined by HPLC.
  • the purity of the sample depicted in FIG. 1 is 99.58%. Impurities are below 0.25% as determined by HPLC. Typically, as found in the sample depicted in FIG. 1 , impurities are 0.02%, 0.04%, 0.15% and 0.19%.
  • FIG. 1 is the XRD spectrum of compound (1b).
  • X-axis 2-theta value (deg).
  • Y-axis intensity (cps). Three distinct peaks can be discerned:
  • Source X-ray tube Target: Cu Tube Voltage: 40 kV Tube Current: 40 mA Start Angle: 2 deg Stop Angle: 40 deg Scan Axis: ⁇ 2 Theta/Theta Method: Continuous Counting Units: CPS (Counts per sec) Scan Speed: 2 deg/min Div slit: ⁇ 2 ⁇ 3 deg DHL slit: ⁇ 10 mm Scattering slit: ⁇ 2 ⁇ 3 deg Rec slit: ⁇ 0.3 mm HPLC Analysis
  • phenylthio pneumocandin B 0 amine (1.6 L; 17.3 g phenylthio pneumocandin B 0 amine; 15 mmol; 44 vol % water) was cooled to ⁇ 10° C. Under stirring ethylenediamine (EDA; 320 mL; 4.7 mol) was added in 20 minutes between ⁇ 10 and ⁇ 3° C. At the start immediately a white precipitate was formed, which dissolved later on. The reaction mixture was stirred for 15 hours at 21-22° C. Additional EDA (170 mL; 2.5 mol) was added at 10-20° C. and stirring at ambient temperature was continued for 31 hours.
  • EDA ethylenediamine
  • Silica gel 100 C 18 (900 g) was suspended in 75% acetonitrile (2 L). The mixture was placed in a column (height 19.6 cm; internal diameter 10 cm). A bed-volume of 1540 mL was obtained. The column was first washed with 3 bed-volumes 100% acetonitrile and then equilibrated with 3 bed-volumes 0.15% acetic acid in water with a flow of 80 mL ⁇ min ⁇ 1 at approximately 1 bar. The caspofungin solution (9.45 L) as prepared above was used as such for loading on the column. The flow rate was ⁇ 50 mL ⁇ min ⁇ 1 . The flow was adjusted to keep the pressure below 5 bar. The linear flow rate was ⁇ 0.6 cm ⁇ min ⁇ 1 .
  • the loading capacity was 10 g caspofungin diacetate per L resin (12 g total caspofungins per L).
  • the column was washed with 0.15% acetic acid in water (3.2 L) with a flow rate of 70 mL ⁇ min ⁇ 1 after which the column was eluted with different solvent compositions at the same flow rate:
  • a column with a diameter of 10 cm was filled with Amberchrom XT30 resin giving a bed volume of 628 mL and a bed height of 8 cm.
  • the column was equilibrated with 0.15% acetic acid. Loading, washing, and elution were carried out in two subsequent runs. After the first run the column was equilibrated with 0.15% acetic acid. The eluate was monitored continuously with UV (280 nm and 254 nm).
  • the samples were dissolved in MeOD by vortexing. The samples were measured at 600 MHz using a delay of 30 s at 300K. The spectra that were used for the calculation of the impurities in the aromatic region were measured using a delay of 5 s and 256 scans to enhance the signal to noise ratio. The analysis was carried out in duplo. Caspofungin was quantified using the tyrosine signal at 7.15 ppm. See Table 5 for results.

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US13/876,227 2010-09-28 2011-09-26 Method for isolating a cyclohexapeptide Active 2032-01-01 US9056897B2 (en)

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EP10180641 2010-09-28
EP10180641 2010-09-28
EP10180641.2 2010-09-28
PCT/EP2011/066650 WO2012041801A1 (en) 2010-09-28 2011-09-26 Method for isolating a cyclohexapeptide

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9636407B2 (en) 2012-11-20 2017-05-02 Fresenius Kabi Usa, Llc Caspofungin acetate formulations

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Publication number Priority date Publication date Assignee Title
KR101944512B1 (ko) * 2011-04-20 2019-01-31 셀리아 파마슈티칼즈 에이피에스 미카펀진의 정제 방법
CN102746384B (zh) * 2011-04-22 2016-01-20 上海天伟生物制药有限公司 一种高纯度的卡泊芬净或其盐及其制备方法和用途
EP2992003B1 (en) 2013-05-02 2017-01-25 DSM Sinochem Pharmaceuticals Netherlands B.V. Method for isolating caspofungin
CN104163855B (zh) * 2013-05-16 2017-10-17 重庆圣华曦药业股份有限公司 一种卡泊芬净中间体及其盐的分离纯化方法
CN104250290A (zh) * 2013-06-28 2014-12-31 博瑞生物医药技术(苏州)有限公司 一种卡泊芬净或其盐的分离纯化方法
CN105254721B (zh) * 2014-05-13 2021-05-18 江苏豪森药业集团有限公司 米卡芬净的纯化转盐方法
CN103965298B (zh) * 2014-05-23 2016-08-10 浙江海正药业股份有限公司 一种阿尼芬净的纯化方法
CN108276478B (zh) * 2014-05-29 2021-09-28 上海天伟生物制药有限公司 环肽类化合物的晶体及其制备方法和用途

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US4310518A (en) 1979-10-31 1982-01-12 Merck & Co., Inc. Cyclic hexapeptide somatostatin analogs
WO2005026323A2 (en) 2003-09-05 2005-03-24 Merck & Co., Inc. Stationary phases and a purification process using the stationary phases
WO2009142761A1 (en) 2008-05-21 2009-11-26 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Caspofungin bo free of caspofungin co
WO2009158034A1 (en) 2008-06-25 2009-12-30 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Caspofungin free of caspofungin impurity a
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9636407B2 (en) 2012-11-20 2017-05-02 Fresenius Kabi Usa, Llc Caspofungin acetate formulations

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WO2012041801A1 (en) 2012-04-05
CN103180336A (zh) 2013-06-26
EP2621941A1 (en) 2013-08-07
CN103180336B (zh) 2016-06-15
CN106397543A (zh) 2017-02-15

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